Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Cytokinesis wikipedia , lookup
Cell culture wikipedia , lookup
Endomembrane system wikipedia , lookup
Cell encapsulation wikipedia , lookup
Cellular differentiation wikipedia , lookup
Organ-on-a-chip wikipedia , lookup
Tissue engineering wikipedia , lookup
Signal transduction wikipedia , lookup
British Journal of Medicine & Medical Research 16(12): 1-10, 2016, Article no.BJMMR.27019 ISSN: 2231-0614, NLM ID: 101570965 SCIENCEDOMAIN international www.sciencedomain.org Biology of Tooth Movement Anand Sabane1, Amol Patil1*, Vinit Swami1 and Preethi Nagarajan1 1 Department of Orthodontics, Bharati Vidyapeeth Deemed University, Pune, Maharashtra, India. Authors’ contributions This work was carried out in collaboration between all authors. Authors AS, VS and PN collected the articles, designed the review and wrote the article. Author AP corrected and rearranged the article and the entire review. All authors read and approved the final manuscript. Article Information DOI: 10.9734/BJMMR/2016/27019 Editor(s): (1) Joao Paulo Steffens, Department of Stomatology, Universidade Federal do Parana, Brazil. (2) Karl Kingsley, Biomedical Sciences and Director of Student Research University of Nevada, Las Vegas - School of Dental Medicine, USA. (3) Salomone Di Saverio, Emergency Surgery Unit, Department of General and Transplant Surgery, S. Orsola Malpighi University Hospital, Bologna, Italy. Reviewers: (1) Ashetty Nj, Manipal College of Dental Sciences, Manipal University, Mangalore, India. (2) D. S. Pushparani, Srm University, India. (3) A. Bhagyalakshmi, JSS University, India. (4) Fernando Lima Martinelli, Pontifical Catholic University of Rio Grande do Sul, Brazil. Complete Peer review History: http://sciencedomain.org/review-history/15417 th Review Article Received 16 May 2016 Accepted 27th June 2016 th Published 17 July 2016 ABSTRACT Research in the field of cellular and molecular biology is relatively lagging in comparison to mechanical advances in the field of orthodontics. Even though the mechanical advances are used quite carefully during orthodontic tooth movement, traumatic effects on the periodontium have not been totally prevented. This may be because of a lack of complete understanding of the cellular complexities. Proper understanding of cellular and molecular biology will help design mechanics that will produce maximum benefits during tooth movement with minimal tissue damage. The rate of tooth movement depends on the rate at which bone remodels and hence, better knowledge of specific biochemical pathways in individual patients will provide a key to predicting how well teeth respond to mechanical forces. This in turn will provide for better tooth movement and faster treatment procedures. The pressure tension theory as well as the bioelectric theory have been discussed in detail along with various chemical mediators with the lipo-oxygensase pathway as well as they cyclooxygenase pathway. Role of neurotransmitters and vasoactive amines along with mechano-transduction has been discussed in the review. These predictors, however, need further work to validate reliability. _____________________________________________________________________________________________________ *Corresponding author: E-mail: [email protected], [email protected]; Sabane et al.; BJMMR, 16(12): 1-10, 2016; Article no.BJMMR.27019 Keywords: Biology; tooth movement; pressure tension theory; mechanotransduction. There are two possible control elements that form two major theories of orthodontic tooth movement. They are: 1. INTRODUCTION The movement of a tooth occurs due to the translocation of the tooth from one position in the jaw to another. Extrinsic forces applied to the crown of the tooth during physiological, therapeutic or pathological processes cause tooth movement [1]. Teeth can be repositioned and retained in a new position in the jaw using orthodontic appliances, through the intervention of the cells of the periodontium. Research in the field of cellular and molecular biology is relatively lagging in comparison to mechanical advances in the field of orthodontics. Even though the mechanical advances are used quite carefully during orthodontic tooth movement, traumatic effects on the periodontium have not been totally prevented. This may be because of a lack of complete understanding of the cellular complexities. 1) Biological Electricity. 2) Pressure – Tension in the periodontal ligament (PDL). 2.1 The Bio – Electric Theory This theory explains that the electric signals that are produced when alveolar bone bends or flexes, are at least partly responsible for tooth movement. Electric signals that might initiate tooth movement initially were thought to be Piezoelectric. Piezoelectric signals characteristics [8]: have two unusual 1. A quick decay rate – when force is applied, a piezoelectric signal is created, that quickly dies away to zero even though the force is maintained. 2. The production of an equivalent signal opposite in direction when force released. Proper understanding of cellular and molecular biology will help design mechanics that will produce maximum benefits during tooth movement with minimal tissue damage. The rate of tooth movement depends on the rate at which bone remodels and hence, better knowledge of specific biochemical pathways in individual patients will provide a key to predicting how well teeth respond to mechanical forces. This in turn will provide for better tooth movement and faster treatment procedures. A thorough knowledge of the biochemical mediators of orthodontic tooth movement and their mechanisms will provide a rational for better and effective treatment [1-4]. 2. THEORIES OF TOOTH MOVEMENT Ions in the living bone interact with the electric field generated when the bone bends, causing temperature changes as well as electric signals. The small voltage that is observed is called the “streaming potential” These voltages, though different from piezoelectric signals in dry materials have in common their rapid onset and alterations, Streaming potential could be generated by the application of external electric fields. Sustained force of the type used to induce orthodontic tooth movement does not produce prominent stress generated signals. A second type of electric signal can be observed in bone that is not being stressed, which is called the “bioelectric potential”. Metabolically active bone produces electro negative changes that are generally proportional to their activity. Cellular activity can be modified by adding exogenous electric signals, which affect cell membrane receptors, membrane permeability or both. Alveolar bone resorption and deposition during orthodontic tooth movement is a cell – mediated process regulated by various factors. However the mechanisms involved in conversion of OF (Orthodontic Force) into biologic activity are not completely understood. Baumrind and Grimm demonstrated that alveolar bone deflection is routinely produced by orthodontic force (O.F). and these forces are accompanied by consequential changes in the periodontal ligament [9]. On the other hand, Hellar and Nanda tested the role played by Therefore an effort is made through this review titled “Biology of tooth movement” to provide an opportunity for the reader to understand and update the knowledge on the latest research on biological changes occurring at the molecular and genetic level [5-7]. This would in turn help an orthodontist in delivering better mechanics, producing quicker tooth movement with minimum tissue damage and maximum comfort to the patient. 2 Sabane et al.; BJMMR, 16(12): 1-10, 2016; Article no.BJMMR.27019 2.2.1 Messenger systems periodontal fibers in transmitting stress generated by orthodontic forces to bone. Epker and Frost [10] documented changes in the curvature of bone surfaces, caused by loading and correlated these changes with specific cellular response [11]. Zengo and associates investigated the nature of electro-chemical relationship associated with the dentoalveolar complex using simulated OF. Both in-vivo studies indicated that areas that are electro-negative were characterized by elevated osteoblastic, activity and areas of electropositivity were characterized by elevated osteoclastic activity [12]. The cells in each system have the ability to produce a large number of chemical agents possessing stimulatory effects or inhibitory effects on other neighboring cells through the synthesis and release of potent substances that modulate cellular behavior. “The Primary Stimulus” or “First Messengers” may alter all activity through the plasma membrane. The responsive cells possess receptors for these substances. Their interactions lead to a transient increase in the intracellular level of “Second Messengers” followed by enzymatic phosphorylation, protein synthesis, cellular events that regulate cyclic adenosine mono phosphate (cAMP) production (Second Messenger) and cell response (Chart 1). The agonists, primary stimulus or first messenger such as hormones or mechanical forces (Orthodontic Force) may alter activity through the plasma membrane. The production of second messenger (cAMP) pathway is regulated by stimulatory (Rs) or inhibitory (Ri) receptors. Davidovitch and associates were able to show that accelerated Orthodontic tooth movement resulted when exogenous electric current was administrated in conjunction with orthodontic forces, which further increased cellular response to electrical stimulation [13,14]. This suggests that the piezoelectric response propagated by bone bending incident to of application may be functioning as “Cellular first messenger.” 2.2 The Pressure Tension Theory This theory explains the cellular changes produced by chemical messengers during tooth movement. This is mainly because of alteration in blood flow through the PDL. The alteration in blood flow quickly creates changes in the environment. For example, oxygen levels would fall in the compressed area but might increase on the tension side and the relative proportions of other metabolites would also change in a matter of minutes. Orhan Tuncay and Daphane observed that low oxygen tension causes increased cellular proliferation and decreased Adenosine triphosphate (ATP) activity and partial pressure of oxygen (Po2) while hypoxic conditions result in suppressed cellular proliferation and increased ATP activity [15]. These chemical changes acting directly or by stimulating the release of other biologically active agents then would stimulate cellular differentiation and activity. Chart 1. Release of cycli AMP (Secondary messenger) The intra-membranous components that have been shown to mediate effects of the extra cellular stimuli are calcium ions and cell membrane enzymes. This interaction between receptors and their respective proteins i.e stimulatory and inhibitory G proteins (Gs & Gi) stimulate or inhibit Adenylate cyclase. This enzyme helps in the formation of cAMP from ATP. The agents such as Forskolin can activate adenylate cyclase directly. cAMP is known to activate protein Kinase – A, an enzyme responsible for protein phosporylation which In essence, this view of tooth movement shows three stages. a) Alteration in blood flow in the PDL. b) The formation and / or release of Chemical Messengers. c) Cell response. 3 Sabane et al.; BJMMR, 16(12): 1-10, 2016; Article no.BJMMR.27019 causes cell response. Hydrolysis of cAMP into 5 AMP is affected by Phosphodiesterase enzyme (PDE) The concentration of cAMP is maintained by preventing the hydrolysis to 5 AMP in the presence of PDE inhibitors. In support of the second messenger pathway involvement in Orthodontic tooth movement, Davidovitch5 and Shanfield reported that cAMP concentrations were significantly higher in alveolar bone extract taken from orthodontically treated cats as opposed to untreated alveolar bone sample. mobilized from the endoplasmic reticulum. Calcium thus released is responsible for protein phosporylation, which leads to early and sustained cell response. IP3 in turn is either dephosphorylated to free Inositol, which is then recycled into the poshosphatidyl inositol (P.I.) Pathway or phosphorylated to form Tetra Inositol Phosphate. This IP4 may have a role in gating calcium through calcium channels of the membrane. IP4 is a proven mediator of mitogenesis in a variety of cell types. In addition to the production of Ip3, DG is formed, which remains within the plane of the cell membrane and activities protein kinase-C (PKC). Protein kinase-C is an enzyme responsible for protein phosphorylation which leads to cell response. Phospholipids from diacylglycerol in the presence of phospholipids also give rise to Arachidonic acid (Eicosanids). With these developments it became clear that second messengers other than cAMP, such as phospholipid metabolites, i.e. Inositol Phosphate and Diacylglycerol could mediate the effects of mechanical deformation. 2.2.2 Phosphate Inositol (PI) pathway A further “Second Messenger” system was investigated in 1950’s by Hokin and Hokin who showed an increase in Phosphate incorporation into cell membrane phospholipids in response to many stimuli. However, the importance of phospholipids as a messenger system was not fully appreciated until 1980’s when Streb and others demonstrated that, products of InositolLipid breakdown could cause release of intracellular calcium ions. Membrane events that result in the reduction of Inositol phosphates are similar to those for generation of cAMP. In this pathway, agonist binds cell surface receptors followed by receptor-G-protein interaction, resulting in the formation of Inositol phosphate. Inositol phosphate in the presence of phospholipids gets converted to phosphotidylinositol biphosphate (Chart 2). 2.2.3 Prostaglandins and tooth movement Prostaglandins were first discovered by Von Euler [16] in 1934. The compound was isolated from human semen and it was believed at that time that the prostate gland was major source. It is now known that prostaglandins are produced by nearly all tissues, but the name has been retained. The ability to stimulate or inhibit tooth movement by addition of exogenous PGE or Indomethacin respectively suggests that mechanical forces are mediated by prostaglandin production. Based largely on this, Yamasaki [17] and co-workers demonstrated that injection of Prostaglandins increased Osteoclast numbers. Cycloxygenase inhibitors such as Indomethacin and other Non steroidal anti-inflammatory drugs (NSAIDs,) which inhibit prostaglandin synthesis, inhibit the appearance of osteoclasts. Further work by Yamasaki showed that local prostaglandin injection could also increase the rate of orthodontic tooth movement in primates. An Animal experiment conducted by Bhalaji [18] (On rabbits) also showed that administration of prostaglandin increased the rate of tooth movement. Chart 2. Inositol pathway 2.2.4 Arachidonic acid pathway The Phosphodiesterase then cleaves IP2 into diacylglycerol (DG) and Inositol Triphosphate with the subsequent release of calcium from intracellular stores. Intracellular calcium ions are An earlier report in a rabbit model found only a significant decrease in osteoclast number and not in the degree of tooth movement. Sandy 4 Sabane et al.; BJMMR, 16(12): 1-10, 2016; Article no.BJMMR.27019 [19,20] and Harris suggested that prostaglandins alone do not account for bone remodeling associated with tooth movement. To sum up the event, as shown by Mostafa et al. [21], it is possible that there are two biologic pathways generated by orthodontic forces (Chart 4): Leukotrienes and Hydroxy Eicosa Tetra-enoic acid (HETE’s) produced from the same substrate (Arachidonic acid) could account for this discrepancy. It has been demonstrated that these inflammatory modulators potentially resorb bone. Leukotrienes, which are also metabolites of Arachidonic acid, were originally demonstrated in leukocytes and were called leukotrienes. It is possible then, since prostaglandins are not fully responsible for bone remodeling associated with tooth movement, lipoxygenase products may also be involved. A rat orthodontic model has been used to demonstrate that inhibition of leukotriene synthesis can significantly reduce orthodontic tooth movement. Both prostaglandins and leukotrienes have a common parent substrate (Arachidonic acid), which is released from the phospholipids of the cell membrane by the action of phospholipase enzyme. (Phospholipids are produced by diacylglycerol). However, factors controlling these events may both be mediated by intracellular alterations in the cyclic nucleotides. The following sequence of events is considered. First, activation of the enzyme phospholipase with subsequent release of Arachidonic acid results in increased cAMP production. Second, there is also an increase in intracellular calcium and stimulation of DNA Synthesis. Arachidonic acid is metabolized by cyclo-oxygenase enzymes producing PG and Thromboxanes. Metabolism through lipooxygenase pathway results in production of leukotrienes and HETE’s (Hydroxy Eicosa Tetraenoic acid) (Chart 3). Pathway – I: Represents a more physiologic response that may be associated with normal growth and remodeling. Pathway – II: Represents the production of a tissue inflammatory response generated by the Orthodontic Force. Chart 4. Biologic pathways generated by orthodontic forces Pathway – I: From the Pathway – I It can be explained that Orthodontic Force creates pressure and tension ultimately leading to bone bending. Since collagen fibers possess piezoelectric properties, the primary response to orthodontic force is the generation of tissue bioelectric polarization in response to bone bending. Alternatively, it has recently been demonstrated by Somjen et al. that bone cells maintained in culture release prostaglandins in response to pressure. It is not clear whether piezoelectric effects themselves stimulate the observed prostaglandin synthesis or whether alternative independent events are involved. However, there is circumstantial evidence that electrical stimulation elicits prostaglandin synthesis. It is clear from the literature that both prostaglandin synthesis and membrane electrical polarization, by the piezoelectric process act on the cell surface cyclic nucleotide pathway, generating changes in the levels of cAMP. So far, the events described do not take into Chart 3. Arachidonic pathway 5 Sabane et al.; BJMMR, 16(12): 1-10, 2016; Article no.BJMMR.27019 consideration the directional control of tooth movement. It has been demonstrated that during bone bending, areas of convexity assume a positive charge and areas of concavity assume negative change. brought about by the hydrolytic enzyme produced by the lymphocytes, monocytes and macrocytes. 3. ROLE OF NEUROTRANSMITTERS IN ORTHODONTIC TOOTH MOVEMENT Interestingly, it has also been shown that electrically neutral or positive areas promote osteoclast activity and zones of electro negativity support osteoblastic activity. This may explain how matrix change polarization contributes to the directional control of orthodontic bone remodeling. In addition, the charged matrix may activate membrane polarization in turn effecting cAMP levels. It has been recently suggested by Rodman and Martin that bone formation and resorption are synchronized by a diffusible product produced by the osteoblast and named it a “Coupling Factor”. The presence of such a coupling factor would indicate that perhaps the osteoblast responds to the initial environmental condition and subsequently regulates osteoclastic activity. This would provide for a mechanism in which net bone formation equals net bone resorption. The coupling factor could then explain the observation that, both bone resorption and formation occurs in areas of pressure and tension, and in the opposite direction thus maintaining the alveolar bone plate thickness. Another outcome of the physical distortion by forces on the para dental tissues is its effect on peripheral nerve fibers and terminals. Neuropeptides stored in nerve terminals within the PDL either may be released into the extracellular space as the applied stress persists or stream towards the ganglion (Chart 5). Pathway – II: In pathway – II the tissue injury generated by OF elicits a classic inflammatory response. Inflammatory processes are triggered along with the classic vascular and cellular infiltration. Lymphocytes, monocytes and macrophages invade the inflamed tissue and in all likelihood contribute to prostaglandin release and hydrolytic enzyme secretion. It has been well documented that local inflammatory responses stimulate osteoclastic activity. This increase in osteoclastic activity is believed to be generated by local elevation of prostaglandin and subsequent increase in cellular cAMP. Chart 5. Role of neurotransmitters in orthodontic tooth movement Neuropeptides are distributed widely in many tissues, some of the neuro peptides particularly Substance P (SP), Vasoactive intestinal polypeptide (VIP) and calcitonin gene related peptides (CGRP) have been shown to affect bone cells directly or through their effects on the vascular system by increasing the permeability. Substance P [22] has been identified in dental tissues around the blood vessels in the dental pulp. They are responsible for vasodilatation and extravasation of plasma and migration of leukocytes into extra vascular tissues. When Substance P was incubated for 48 hours with cultured human synoviocytes of arthritic patients, it caused significant elevation of prostaglandin-E (PGE) and collagenase release into the medium as well as increase in cell proliferation. Vasoactive intestinal polypeptide was first isolated from hog intestinal tissue. It is a potent The strongest evidence for the presence of a chemical mediator released in response to the inflammatory reaction is the fact that bone remodeling persists for several days after cessation of OF. The inflammatory response is also characterized, by hydrolytic enzyme secretion. This has important relevance to connective tissue turnover. It is believed that collagenase exists in an inactive form and may be activated plasminogen activator, which digest the osteoid, exposing the mineralized matrix and allowing the osteoclast to act. This has been 6 Sabane et al.; BJMMR, 16(12): 1-10, 2016; Article no.BJMMR.27019 vasodilator shown to stimulate bone resorption in vitro through a cAMP related mechanism. VIP in the cat dental pulp has been reported. It is possible therefore to visualize a complex set of events that might arise either from distorting a cell, cell membrane, or extracellular matrix mechanically or by inducing a change in cell shape with hormones and growth factors. To date there is little published work regarding changes in the cytoskeleton with mechanical forces, but Banes et al found decrease in Tubulin and suggested that this may have a role in mediation of mechanical stress. After discussing the basic biochemical reaction to O.F. let us go into the queries put in the beginning of the talk. 4. SHAPE CHANGE IN CELLS 4.1 Mechanism for the Transduction of Mechanical Forces The development of techniques to isolate and culture cell types and methods of deforming cell layers or altering cell shape have suggested that a definite relationship exists between cell shape and metabolic activity. Folkman and Mascona showed that flattened cells synthesize more DNA than rounded cells. Aggler and Frich produced evidence that catabolic rather than anabolic events are associated with rounded cells. Prostaglandins and parathyroid hormone (PTH) induced shape change in bone cell culture. It is conceivable then that in pressure sites, cells are rounded and have catabolic effects and in tension sites cells are flattened and are therefore in an anabolic or in a synthetic mode. It is important to realize that shape change by cultured cells in vitro in response to various hormones and growth factors may not necessarily occur in vivo. 5. HOW DO CELLS DISTINGUISH BETWEEN TENSION AND PRESSURE (COMPRESSION)? If bone cells cannot distinguish between tensile and a compressive mechanical stress, how can bone resorption takes place on the compression side of the alveolar bone during orthodontic tooth movement. At the “Biology of Tooth Movement” conference held at Farmington in Nov. 1986 it was suggested that the answer was likely to be found in the field of cytokine biology. According to this hypothesis, formation or resorption of bone depends on i) the cytokines produced locally by mechanically activated cells and ii) the functional state of the available target cells. As we know, cells communicate among themselves as well as with other cells through the synthesis and release of potent substances that modulates cellular behavior. The responsive cells possess receptors for these substances and their interaction leads to a transient increase in the intracellular level of “Second Messengers” followed by enzymatic phosporylation and protein synthesis. 4.2 Cytoskeleton Matrix Interactions Several researchers have shown that shape changes in cells could be brought about by non – chemical means and this was mainly because of the reorganization of the cytoskeletal protein. The three main components of the cytoskeleton are i) Microtubules, ii) Microfilaments and iii) Intermediate filaments Microfilaments are perhaps the best situated of the three systems to detect these changes. The major subunit protein of the microfilaments is Actin. There are, however, many associated proteins such as myosin, Tropomyosin, Vinculin, and Talin. Microfilament bundles terminate at specialized Talin sites of the cell membrane forming a junctional complex with the extracellular matrix. These tight adhesions are known as Focal Contacts or Adhesion Plaques. The cell membrane integral proteins termed Integrins span the cell membrane from the cytoplasm to the extracellular matrix. Integrins do not bind directly to microfilaments such as ACTIN, but are dependent on associated proteins for this function (e.g. Fibronectin extracellularly and Talin intracellularly). Actin Vinculin bind to this Talin – Integrin complex. 5.1 Cytokines as Mediators of Mechanically Induced Bone Remodeling Cytokines [8] are short – range soluble mediators released from cells, which modulate the activity, of other cells. The first ones identified were lymphokines produced by lymphocytes. Then it was thought that lymphocytes were the only cells that could produce such factors, and hence they named them as “lymphokines”. It is now known that many different cell types can produce these agents and the term cytokines is used. Inflammatory cells produce numerous cytokines, which mediate various stages of inflammation. Well over 50 cytokines have been described till 7 Sabane et al.; BJMMR, 16(12): 1-10, 2016; Article no.BJMMR.27019 date. Some of Interleukin – 1 Necrosis Factor, implicated in the process in vitro. these cytokines particularly alpha, and 1 beta, Tumor Gamma Interferon have been mediation of bone remodeling Resorptive signals may be transmitted to osteoclasts by the cytokines, which are produced by the osteoblasts. The cytokines may either activate osteoclast directly or promote their recruitment and differentiation from their precursor cells. Thus osteoblasts are no longer regarded simply as bone forming cells. Whether all osteoblasts are capable of presenting resorptive signals to osteoclasts or their precursor cells is not clear. It is possible that a population of ‘Helper’ osteoblasts exists in bone distinct from those involved in matrix synthesis, whose principle function is to regulate resorption. Alternatively, all osteoblasts may have the potential to act as helper cells act some stage in their life cycle. Once osteoid formation has ceased, the surface resting osteoblasts acquire the ability to respond to resorptive signals. Interleukin – 1 originally was defined as a monocyte / macrophage product with numerous biological functions such as bone resorption, and fibroblast proliferation. Interleukin – 1 promotes release of collagenase and patients with chronic gingivitis. It was also detected in the periodontal tissues of cat canine teeth after the application of a tipping force, which provided the first experimental evidence to support the hypothesis. 5.2 Cytokines and Interaction between Osteoblast and Osteoclast: How do Cytokines Mediate Mechanically Induced bone Remodeling? An additional theory has been put forward that in response to PTH, osteoblasts secrete a soluble activator for osteoclasts known as Osteoclast Activating Factor (OAF). Now it is clear that although osteoclast is the principle bone – resorbing cell, the osteoblast is now recognized as the cell, which controls both formative and resorptive phase of the bone remodeling cycle. Therefore whether bone formation or resorption predominates at a particular site is determined by the cytokines produced locally by mechanically activated cells as well as the functional state of the available target cells. According to Sandy & Meghji [15,16], in addition to the various above mentioned mechanisms by which osteoclastic bone resorption is stimulated, osteoblasts are also involved in signal transmission in response to binding of hormones like PGE2 or parathormone to a receptor on the osteoblast. Osteoblasts produce a soluble mediator for activation and recruitment of osteoclasts. It has been realized that osteoblasts have the receptors for PGs, PTH and Vit D, but not osteoclasts. The transmission of signals from osteoblasts to osteoclasts occurs in two ways. Osteoblasts respond to systemic and local agents by producing collagenase. Osteoclasts cannot / do not resorb bone unless the surface osteoid layer is removed. Therefore osteoblasts might facilitate bone resorption through mineral exposure. The osteoblasts, having recognized the resorptive signal somehow transmit it to the osteoclasts. Rodman and Martin hypothesized that bone resorbing agents such as PTH may induce a change in shape of the osteoblasts which would facilitate the access of osteoclasts to bone surface. Thus a low concentration of PTH promotes bone formation, but at high concentration will facilitate bone resorption. Resting bone surfaces are covered by a thin layer of non – mineralized osteoid, which protects the underlying mineralized bone from uncontrolled osteoclastic action. This is supported by observations on resting bone, where osteoblasts lie flat on the bone surface. When PTH stimulates these cells they change shape, becoming more round and thus exposing the underlying minerals. There is now good evidence that removal of this osteoid is brought about by collage production by the osteoblasts. This indicates that bone resorption occurs as a tightly defined event with the osteoblasts controlling the critical phase. This mechanism is unlikely to be the major regulatory factor because it can only influence the activity of already differentiated osteoclasts. Also, they produce matrix metalloproteinase (MMP’s) for breakdown of nonmineralised osteoid layer. Osteoclasts can then remove bone after the surface, osteoid layer is removed by the MMP’s and mineralized matrix is exposed. Osteocytes i.e. osteoblasts trapped in the trapped in the mineralized bone matrix are also thought to play a role as mechanical sensors detecting mechanical loading of bone which results in cellular response. Matrix metalloproteinases [23] are extracellular matrix degrading metallo enzymes collectively known as MMP's. Endogenous inhibitors exist for these metallo enzymes & are known as tissue inhibitors of metalloproteinase (TIMP's). These metallo 8 Sabane et al.; BJMMR, 16(12): 1-10, 2016; Article no.BJMMR.27019 enzymes are called metallo, because they depend on Zn++ and Ca++ for their activity. They act at neutral pH and digest the major macro molecules of connective tissues. Tissue breakdown occurs where MMP's are in excess of TIMP's. The significance of these enzymes in orthodontic tooth movement is that the MMP's and TIMP's are both increased during mechanical deformation of sutures. REFERENCES 1. 2. The Osteoclast apart from its osteolytic function also plays an important role in the development and growth of bone by releasing polypeptide growth factors from the extracellular mineralized matrix [24-26]. These factors are generally referred to as Bone Derived Growth Factors (BDGF) and are known to include Bone Morphogenetic Proteins (BMP) Platelet Derived Growth Factor (PDGF) and Transforming Growth Factor (TGF) etc. 3. 4. 6. CONCLUSION The concepts involving the molecular and microscopic tissue changes that accompany tooth movement have undergone path breaking changes. Bone bending and generation of piezoelectric signals were earlier thought of as important keys to explaining cellular differentiation and bone remodeling. Later research substantiated the concepts of tooth movement as a result of an inflammatory reaction in response to applied forces and the vital role of chemical mediators such as cytokines, interleukins and growth factors. Recent research also sheds light on the role of RANKL and RANKL receptors as well as osteoprotegerins in establishing a balance between osteoblasts and activated osteoclasts thereby controlling the amount as well as direction of bone remodeling Biology of tooth movement being such an enormous and interesting platform can surely accomodate several new studies and research endeavors. In summary, despite its apparently solid and inert form, bone is probably the most dynamic and complex of body tissues. 5. 6. 7. 8. 9. 10. CONSENT It is not applicable. 11. ETHICAL APPROVAL It is not applicable. 12. COMPETING INTERESTS Authors have interests exist. declared that no competing 9 Oswal D, Sable RB, Patil AS, Moge A, Aphale S. Levels of matrix metalloproteinase-7 and osteopontin in human gingival crevicular fluid during initial tooth movement. APOS Trends Orthod. 2015;5:77-82. Patil AS, Sable RB, Kothari RM. An update on transforming growth factor–β (TGF-β): Sources, types, functions and clinical applicability for cartilage/bone healing. J Cell Physiol. 2011;226:3094-3103. Patil AS, Sable RB, Kothari RM. Role of Insulin-like growth factors (IGFs), their receptors and genetic regulation in the chondrogenesis and growth of the mandibular condylar cartilage. J Cell Physiol. 2012;227:1796-1804. Patil AS, Sable RB, Kothari RM. Occurrence, biochemical profile of vascular endothelial growth factor (VEGF) isoforms and their functions in endochondral ossification. J Cell Physiol. 2012;227:1298-1308. Mundhada AA, Kulkarni UV, Swami VD, Deshmukh SV, Patil AS. Craniofacial Muscles-differentiation and Morphogenesis. Annual Res Rev Biol. 2016;9(6): 1-9. Doshi RR, Kulkarni UV, Shinde S, Sabane AV, Patil AS. Role of genes in odontogenesis. Brit J Med Medical Res. 2016;14(6):1-9. Patil AS, Merchant Y, Nagarajan P. Tissue engineering of craniofacial tissues. J Reg Med Tiss Eng. 2013;2:1-19. Proffit WR, Fields HW, Sarver DM. Contemporary orthodontics. 3rd ed. St. Louis: Mosby Elsevier. 1999;296-308. Grimm FM. Bone bending, a feature of orthodontic tooth movement. Am J Orthod. 1972;62(4):384–93. Epker BN, Frost TN. Correlation of bone resorption and formations with the physical behavior of loaded bones. J Dent Res. 1965;44:31-41. Heller IJ, Nanda R. Effect of metabolic alteration of periodontal fibers on orthodontic tooth movement. An experimental study. Am J Orthod. 1979;75(3):239-58. Zengo AN, Pawluk RJ, Bassett CA. Stress induced bioelectric potentials in the dentoalveolar complex. Am J Orthod. 1973;64(1):17-27. Sabane et al.; BJMMR, 16(12): 1-10, 2016; Article no.BJMMR.27019 13. Davidovitch Z, Finkelson MD, Steigman S, 19. Sandy JR. Tooth eruption and orthodontic Shanfeld JL, Montgomery PC, Korostoff E. movements. Br Dent J. 1992;172:141-9. Electric currents, bone remodeling & 20. Meghji S. Bone remodeling. Br Dent J. orthodontic tooth movement. I. The effect 1992;172:235-42. of electric currents on periodontal cyclic 21. Mostafa YA, Weaks-Dybvig M, Osdoby P. nucleotides. Am J Orthod. 1980;77(1):14Orchestration of tooth movement. Am J 32. Orthod. 1983;83:245-9. 14. Davidovitch Z, Finkelson MD, Steigman S, 22. Davidovitch Z, Nikolay OF, Nyan PW, Shanfield JL. Neurotransmitters, cytokines Shanfeld JL, Montgomery PC, Korostoff E. and the control of alveolar bone Electric currents, bone remodeling and remodeling in orthodontics. Dent Clin North orthodontic tooth movement. II. Increase in Am. 1988;32(3):411-35. the rate of tooth movement & periodontal cyclic nucleotides level by combined force 23. Tsay TP, Chen MH, Oyen OJ. Osteoclast activation & recruitment on application of and electric currents. Am J Orthod. orthodontic force. Am J Orthod Dentofacial 1980;77(1):33-47. Orthop. 1999;115(3):323-30. 15. Tuncay OC, Ho D, Barker MK. Oxygen 24. Doshi RR, Patil AS. Genes in craniofacial tension regulates osteoblast function. Am J growth. IIOAB J. 2012;3:19-36. Orthod Dentofacial Orthop. 1994;105(5): 25. Patil AS, Sable RB, Kothari RM. Genetic 457-63. expression of MMP-1 and MMP-13 as a 16. Samuelsson B, Granstrom E, Hamberg M, function of anterior mandibular Hammarstrom S. Prostaglandins. Ann Rev repositioning appliance on the growth of Biochem. 1975;44:669-94. mandibular condylar cartilage with and 17. Yamasaki K, Miura F, Suda T. without administration of IGF-1 and TGF-b. Prostaglandin as a mediator of bone Angle Orthod. 2012;82:1053-1059. resorption induced by experimental tooth 26. Patil AS, Sable RB, Kothari RM. Genetic movement in rats. J Dent Res. expression of Col-2A and Col-10A as a 1980;59(10):1635-42. function of administration of IGF-1 & TGF18. Bhalaji SI, Shetty SV. The effect of β with and without anterior mandibular prostaglandin E2 on tooth movement in repositioning appliance on the growth of young rabits. J Ind Orthod Soc. mandibular condylar cartilage in young 1996;27:85-92. rabbit. Open J Stomatol. 2013;3:6-13. _________________________________________________________________________________ © 2016 Sabane et al.; This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Peer-review history: The peer review history for this paper can be accessed here: http://sciencedomain.org/review-history/15417 10